1,N6 -etheno-5&#39;-adenosine carboxamides for increasing coronary sinus partial pressure of oxygen

ABSTRACT

Amides of 1,N 6  -Etheno-5&#39;-adensine carboxylic acid represented by the formula ##SPC1## 
     Wherein R 1  and R 2  each are hydrogen, loweralkyl, loweralkenyl, loweralkynyl or cycloalkyl, and R 3  and R 4  each are hydrogen, acyl, or R 3  and R 4  taken together form an isopropylidene or benzylidene moiety; and the pharmaceutically acceptable acid addition salts thereof. 
     The compounds wherein R 3  and R 4  are hydrogen are useful in treating cardiovascular disorders and are particularly useful as anti-anginal and anti-hypertensive agents. Compounds wherein R 3  and R 4  are acyl or when taken together form an isopropylidene or benzylidene moiety are intermediates useful in the preparation of the final products. (R 3  and R 4  = hydrogen).

This is a division of application Ser. No. 317,326 filed Oct. 21, 1972,now U.S. Pat. No. 3,830,796 issued Aug. 20, 1974.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to adenosine derivatives, to therapeuticcompositions containing such derivatives, to methods of preparing andusing the novel compounds and to intermediates useful in the preparationof such compounds.

The compounds of this invention are represented by the formula ##SPC2##

Wherein R₁ and R₂ each are hydrogen, loweralkyl, loweralkenyl,loweralkynyl or cycloalkyl, and R₃ and R₄ each are hydrogen, acyl, or R₃and R₄ taken together form an isopropylidene or benzylidene moiety; andthe pharmaceutically acceptable acid addition salts thereof.

The term "loweralkyl" as used herein, refers to both straight andbranched chain alkyl radicals containing from 1 to 6 carbon atoms,including methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,tert-butyl, iso-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl and thelike.

"Loweralkenyl" refers to the C₂ and C₅ alkyl groups, as defined above,from which a hydrogen atom has been removed from each of two adjacentcarbon atoms to produce ethylenic unsaturation; e.g., vinyl, allyl,methallyl, 1-pentenyl and the like.

"Loweralkynyl" refers to the C₂ to C₅ alkyl groups as defined above,from which 2 hydrogen atoms have been removed from each of two adjacentcarbon atoms to produce acetylenic unsaturation such as ethynyl,propargyl, 2-butynyl, 1-pentynyl and the like.

The term "cycloalkyl" refers to C₃ and C₆ cycloalkyl groups, namely,cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "pharmaceutically acceptable acid addition salts" refers tonon-toxic salts prepared by reacting the amide with the appropriateorganic or inorganic acid, or by utilizing an acid addition salt of theappropriate intermediate. Representative salts include thehydrochloride, hydrobromide, sulfate, bisulfate, acetate, valerate,oleate, laurate, borate, benzoate, lactate, phosphate, tosylate,citrate, maleate, succinate, tartrate, napsylate and the like.

The term "acyl" refers to acetyl, propionyl, butyryl and the like.

The compounds of this invention are useful as antianginal agents atdosages of from 0.1 to 10 mg./kg. of body weight daily.

The anti-anginal activity was first established by measuring theincrease in coronary sinus partial pressure of oxygen (pO₂) according tothe method of Schoepke et al., Pharmacologist 8: 204 (1966).

In addition to their cardiovascular activity, the compounds also exhibitcentral nervous system depressant activity at dosages of from 0.1 to 10mg./kg. of body weight in test animals.

Generally speaking, the compounds of this invention are prepared byreacting the corresonding adenosine-5'-carboxylic acid ester withchloroacetaldehyde. The amides can be prepared by converting2',3'-isopropylidene adenosine-5'-carboxylic acid (prepapred from2',3'-isopropylidene adenosine according to the method described byHarmon et al., CHEM. IND. 1969, 1141) to the corresponding acidchloride, and reacting the acid chloride with an appropriate amine ofthe formula R₁ R₂ NH, followed by hydrolytic cleavage of theisopropylidene group, according to the following reaction scheme:##SPC3##

The following examples further illustrate this invention:

EXAMPLE 1 Preparation of Adenosine-5'-(N-ethyl) Carboxamide

Freshly prepared 2',3'-isopropylidene adenosine-5'-carboxylic acidchloride (prepared from 6.4 g. of 2',3'-isopropylidene-5'-carboxylicacid) was stirred with excess of dry liquid ethyl amine at -50° to -35°.The clear red-orange solution was allowed to warm up to room temperatureand kept at this temperature for 15 hours. At the end of this period theexcess of ethyl amine had evaporated off. The residue was trituratedwith cold aqueous NaHCO₃ solution. The white precipitate was filteredoff and washed with a small amount of cold water to yield 3.1 g. (44.5%)of crude 2',3'-isopropylidene-5'[N-ethyl)-carboxamide] m.p. 225°-227°.R_(f) : 0.72 (silicagel) system: n-BuOH:H₂ O:NH₄ OH (86:14:5). Thisamide was mixed with 80 ml. of IN.HCl and kept at 65° for 45 minutes.The acidic solution was then cooled and basified with NaHCO₃. Themixture was then evaporated to dryness under reduced pressure and theresidue recrystallized twice from absolute ethanol and finally fromwater. The white crystalline product was dried in vacuo for 2 days overP₂ O₅ at 70°-78° to give 0.9 g. (32%) ofadenosine-5'-[N-ethyl)-carboxamide] which melted slowly at 136°-172° andsolidified again at 148°-150° and finally melted at 246°-247° (sharp).[α]_(D) ²⁶.sup.° -163 (CO. 92 in IN.HCl); R_(f) : 0.51 (silicagel).System: n-BuOH:H₂ O:NH₄ OH (86:14:05); NMR (deuterated DMSO) peaks (inppm) at 5.6 (2'-OH, 3'-OH), 7.4 (6C-NH₂): 8.8 (CONH): 3.2 (CH₂ CH₃).

Analysis Calcd. for C₁₂ H₁₆ N₆ O₄ H₂ O: C, 44.17; H,5.53; N, 25.76.Found: C, 44.33; H, 6.01; N, 25.78.

EXAMPLE 2

Adenosine-5'-(N-allyl)carboxamide, m.p. 223-24° dec., was preparedaccording to the method of Example 1, using allyl amine in place ofethyl amine.

Analysis Calcd. for C₁₃ H₁₆ N₆ O₄.H₂ O: C, 46.20; H, 5.36; N, 24.82; O,23.62. Found: C, 46.26; H, 5.58; N, 24.92; O, 24.00.

EXAMPLE 3

Adenosine-5'-(N-cyclobutyl)carboxamide, m.p. 235-37° dec., was preparedaccording to the method of Example 1 using cyclobutylamine in place ofethylamine.

Analysis Calcd. for C₁₄ H₁₈ N₆ O₄ : C, 50.30; H, 5.42; N, 25.14. Found:C, 50.52; H, 5.56; N, 24.72.

EXAMPLE 4 1,N⁶ -Etheno Adenosine-5'-(N-allyl) Carboxamide

Chloroacetaldehyde (26.0 g; 0.1 mole of 30% aqueous solution) was addedto a stirred suspension of adenosine-5'-(N-allyl) carboxamide (3.3 g;0.01 mole) in water (80 ml.) containing a few drops of acetic acid at50°C. In a few minutes the solid dissolved. After 17 hours at 50°C., thereaction solution gave only one fluorescent spot on the TLC paper. Thecloudy reaction mixture was evaporated under reduced pressure. The oilyresidue solidified on trituration with acetone-ether. The amorphoussolid, so obtained, was taken up in a large volume of methanol andstirred with Rexyn-203 [OH]. The methanolic solution was concentrated.Recrystallization of the residue gave the pure product, m.p. 242°-244°.

Analysis Calcd. For c₁₅ H₁₆ N₆ O₄ : C, 52.32; H, 4.68; N, 24.41. Found:C, 52.71; H, 4.69; N,24.33.

EXAMPLE 5

1,N⁶ -Etheno adenosine-5'-(N-cyclobutyl) carboxamide, m.p. 261°-262°,was prepared according to the method of example 4 fromadenosine-5'-(N-cyclobutyl) carboxamide and chloroacetaldehyde.

Analysis Calcd. For C₁₆ H₁₈ N₆ O₄ : C, 53.63; H, 5.06; N, 23.45. Found:C, 53.21; H, 5.18; N, 23.04.

EXAMPLE 6

1,N⁶ -Etheno adenosine-5'-(N-ethyl) carboxamide, m.p. 252°-254°, wasprepared according to the method of Example 4 fromadenosine-5'-(N-ethyl) carboxamide.

Analysis Calcd. for C₁₄ H₁₆ N₆ O₄ : C, 50.60; H, 4.85; N, 25.29. Found:C, 50.27; H, 4.85; N, 25.07.

EXAMPLE 7

Tablets containing 25 mg. of 1,N⁶ Etheno adenosine-5'-(N-allyl)carboxamide and having the following composition are prepared accordingto methods well known in the art.

    ______________________________________                                        1,N.sup.6 -Etheno adenosine-5'-                                               (N-allyl) carboxamide                                                                              10 mg.                                                   Starch               10 mg.                                                   Colloidal Silica     3 mg.                                                    Magnesium stearate   2 mg.                                                    ______________________________________                                    

The compounds of this invention can be formulated into variouspharmaceutical dosage forms such as tablets, capsules, pills and thelike, for immediate or sustained release, by combining the activecompound with a suitable pharmaceutically acceptable carrier or diluentaccording to methods well known in the art. Such dosage forms mayadditionally include excipients, binders, fillers, flavoring andsweetening agents and other therapeutically inert ingredients necessaryin the formulation of the desired pharmaceutical preparation.

We claim:
 1. A method of increasing coronary sinus partial pressure ofoxygen in a patient in need of such treatment comprising administeringan effective coronary sinus partial pressure of oxygen increasing amountof a compound of the formula ##SPC4##wherein R₁ and R₂ each arehydrogen, loweralkyl, a cycloalkyl of 3 to 6 carbon atoms, loweralkenylor loweralkynyl and R₃ and R₄ each are hydrogen, acetyl, propionyl,butyryl, or R₃ and R₄ taken together form an isopropylidene orbenzylidene moiety; or a pharmaceutically acceptable acid addition saltthereof, to said patient.
 2. A method according to claim 1, wherein saidcompound is administered in a dosage of from 0.1 to 10.0 mg./kg. of bodyweight daily.